Robert E. Schoen, MD MPH Associate Professor of Medicine and Epidemiology Division of Gastroenterology University of Pittsburgh Hereditary Colorectal Cancer: From Genetic Testing to Prevention

Colorectal Cancer - Epidemiology 2nd leading cause of CA mortality in U.S. > 130,000 new cases/yr > 48,000 deaths/yr

Estimated Cancer Deaths in U.S Men Women Lung - 31%Lung - 25% Prostate - 13%Breast - 16% Colorectal - 10%Colorectal - 11%

Lifetime Risk of CRC (%) All Races Whites Blacks Male + Female LR DxLR Death SEER,

Etiologic Concepts in CRC

Colorectal Cancer 1%

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Intermediate Endpoint Environment Host Alteration in Large Bowel Epithelium Cancer

Polymorphisms and CRC Risk Low penetrance susceptibility alleles- Meta Analysis APC I1307K1.6 ( ) HRAS1-VNTR2.5 ( ) MTHFR (val/val)0.8 ( ) P53, NAT1, NAT2, GSTM1, GSTT1, GSTP1 exclude >1.7 fold increase Houlston, Gastro 2001;121:282 OR

Consensus Guidelines > = 50  Options:  Annual FOBT  FS q 5 yrs  FOBT + FS  DCBE q 5-10 yr  Colon q 10 yr  + TCE: Colonoscopy or DCBE + FS Gastro. 1997:112;594

Familial CRC

Family Hx - Prospective Study NHS & HPFS (1) 87,000 women; 32,000 men 315 and 148 cases CRC RR = Incidence CRC with fm hx* CRC Incidence CRC with NO fm hx CRC 1 o relative = mother, father, sibs Fuchs et al; NEJM 1994;331:

Family Hx - Prospective Study NHS & HPFS (2) Family Hx CRC reported by 10% of sample RR CRC with Fm Hx = 1.7* * adjusted for diet, ASA, physical activity, cigs, screening endoscopy Fuchs et al; NEJM 1994;331:

Family Hx - Prospective Study NHS & HPFS (3)  Risk with 2 or more 1 o relatives  Risk with family member  55 Conclusions:

AHCPR Guidelines CRC in 1 or 2 (?) FDR Adenomas in FD relative  60 Family Hx Same Options as Avg Risk, but Start at age 40 Gastro 1997:112;594

Germline Mutations

Gastro 2001;121:195

HNPCC - Clinical Characteristics Autosomal dominant, highly penetrant CRC <age 45,  synchro/proximal Polyps - larger, more aggressive; cancers better prognosis Endometrial, ovarian, other CA’s

HNPCC Recognition Early onset cancers Multiple cancers in successive generations Association with other cancers - endometrial

HNPCC - “Amsterdam Criteria” Three or more relatives with CRC, one of whom is 1 o relative of other two CRC in at lest 2 generations One or more cases before age 50

Amsterdam Criteria II 3 Relatives with HNPCC associated CA: CRC, Endometrial, Small Bowel Ureter, Renal Pelvis 1 should be 1 o Relative of other 2 2 successive generations (at least) 1 diagnosed before age 50 FAP excluded Verify Tumors